Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-01-16
1999-01-26
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 12, 514 13, 514 14, 530402, 530313, A61K 3800, A61K 3802, C07K 500, C07K 700
Patent
active
058639004
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to LHRH antagonists and to the systemic and oral delivery of the antagonists by administration of a complex comprising the antagonists linked to vitamin B12 (VB12) or an analogue thereof. More particularly, the invention relates to methods for the synthesis of these complexes.
BACKGROUND OF THE INVENTION
Hypothalamic gonadotrophin releasing hormone (GnRH, also known as luteinizing hormone releasing hormone, LHRH) mediates the regulation of pituitary gonadotrophin synthesis and secretion. Since the initial isolation of LHRH by Schally et al. (1971) numerous analogues have been synthesized, which may be classified according to their acute effects on gonadotrophin release, as either agonists (with enhancement of release) or antagonists, (with inhibition of release). The agonists are characterised by an increase in binding affinity to pituitary LHRH receptors (Loumay et al, 1982, Perrin et al. 1980) and by increased resistance to the proteolytic degradation that rapidly removes native LHRH.
The observation that these potent analogues can induce potentially reversible medical castration has provided a new approach to the treatment of various gonadotrophin dependent disorders, particularly hormone dependent prostate and breast cancer. Two distinct phases in the induction of castration occur. Initially the analogue stimulates the pituitary-gonadal axis causing a transient increase in gonadotrophin and sex steroid secretion in the first two weeks or so. After this period there is a down regulation of pituitary LHRH receptors with subsequent decline in gonadotrophin and sex steroid secretion. The initial stimulation is a substantial drawback to the use of agonists in the treatment of prostatic malignancy as the initial stimulation of testosterone can produce a painful flare of the disease with consequent adverse clinical effects (Eisenberger and Abrams, 1988, Crawford and Davis, 1988). By contrast the first successful synthesis of LHRH antagonists should be advantageous in avoiding the initial flare. First attempts at the production of antagonists led to compounds characterised by undesirable histamine release (Karten and Rivier, 1986, Schmidt et al., 1984, Phillips et al ., 1988). However new antagonists have been developed characterised by improved potency and much less histamine releasing potential eg. Karten and Rivier, 1986. One of the most potent antagonists described to date is the analogue N-Ac-D-Nal(2), D-Phe (pCl), D-Pal(3), Ser, Lys (Nic), D-Lys(Nic), Leu, Lys(iPr), Pro, D-Ala-NH2 (ANTIDE), synthesized by Folkers and Bowers. It is highly potent in rats in inhibiting ovulation (Ljundquist et al;, 1988) and single doses have profound, long lasting inhibitory effects on serum LH concentrations in castrate female cynamologous monkeys (Leal et al, 1988). It has also been shown to be capable of inducing long term chemical castration in intact adult male rats and cynamologous monkeys, and to have an inhibitory effect on tumour growth in the Dunning R3327 prostatic carcinoma model, similar to that of castration (Habenicht et al, 1990). The new antagonist should therefore be of substantial clinical interest in all those conditions in which medical castration is desirable, particularly in the management of prostatic cancer and in various gynaecological disorders (McLachlan et al., 1986). Current administration is limited to the parenteral route. However the dose of analogue that can be delivered by this route is limited due to the poor solubility of the antagonist. Thus clinical trials of the long term effect of ANTIDE have been reduced to doses of 2.5 mg or lower.
The oral route of administration of peptides such as LHRH and its analogues as pharmaceuticals in the treatment of systemic conditions has met with little success. In general the amount of peptide required for successful oral administration has been 100 to 1000 times the dose required for parenteral deliver, thus making the administration of these agents via this route prohibitively expensive. The
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Biotech Australia Pty. Ltd.
Davenport Avis M.
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